Development of hematopoietic cell lineages is tightly controlled by environmental signals, such as cytokines and growth factors. However, little is known about the cell signaling mechanisms by which the hematopoiesis at different stages is regulated by environmental cues. Much attention has been paid to transcription factors that are predominantly expressed in various types of blood cells. The focus of this project is on dissecting the function of Shp-2 in the control of hematopoietic cell development. Murine Shp-2 is a widely expressed cytoplasmic tyrosine phosphatase that was originally cloned by this applicant. Work accomplished in the previous funding period has demonstrated a critical role of Shp-2 in genesis of all blood cell lineages. This is the first example that a cytoplasmic tyrosine phosphatase acts to promote hematopoietic stem/progenitor cell commitment and differentiation. To elucidate the physiological functions of Shp-2 in various types of blood cells, we have generated a conditional Shp-2 knockout (Shp-2flox) allele using the Cre-loxP system. Experiments designed in this competing renewal proposal are to test the hypothesis that Shp-2 plays unique and different functions in lymphoid, myeloid and erythroid cell lineages. Our specific aims are: 1) to assess the role of Shp-2 in T lymphocyte development; 2) to investigate the Shp-2 function in TCR signaling; 3) to determine the requirement of Shp-2 for sustained blood cell production; and 4) to establish and characterize ES cells with a null mutation in the Shp-2 gene. Completion of this work will lead to a better understanding of blood cell development and malignant disorders in the hematopoietic compartment. [unreadable] [unreadable]